PROJECT SUMMARY/ABSTRACT Children hospitalized with severe illness in sub-Saharan Africa are at high risk of morbidity and mortality following discharge from hospital. This risk appears particularly elevated among HIV-infected (HIV+) and HIV-exposed uninfected (HEU) children, a risk that is compounded by the frequency of hospitalizations in these populations. Targeted interventions at hospital discharge could improve recovery, prevent new infections, and reduce rates of re-hospitalization and death. However, identifying effective interventions for HIV+ and HEU children requires a better understanding of the unique mechanisms underlying post-discharge vulnerability in these populations, including the role of dysregulated immune responses to pathogens, persistent immune activation and inflammation, and exposure to and carriage of specific pathogens or antibiotic resistance in those pathogens. The ongoing Toto Bora Trial (R01HD079695) randomizes children aged 1-59 months who have been hospitalized and subsequently discharged from two Western Kenya hospitals to a 5-day course of azithromycin or placebo, and examines risk of morbidity and mortality in the subsequent 6-month period. The trial sites are located in Homa Bay and Kisii counties, which have some of the highest rates of new pediatric HIV infections in the country. A rich data and specimen set is being collected, which includes clinical and sociodemographic data as well as blood, stool, and nasopharyngeal swabs at each study visit. Supplemental funds will be used for new laboratory assays and associated analyses investigating the mechanisms of post-discharge infectious morbidity in HIV+ and HEU children, and to determine whether azithromycin prophylaxis provides differential benefit in these groups. Outcomes from this supplement will directly inform the development of novel management strategies for children affected by HIV.